Endothelins are a family of peptides synthesized and released by endothelial cells in the vascular system, lung, kidney, gastrointestinal cells, and macrophages. The endothelin family is comprised of three 21-α-amino acid isopeptides (ET-1, ET-2, and ET-3). Endothelin-1 (ET-1) has been identified as the major cardiovascular isopeptide.
ET-1 acts in an autocrine and paracrine manner through type A (ETA) and type B (ETB) endothelin receptor subtypes. ETA receptors are located on vascular smooth muscle cells and their activation mediates vasoconstriction and mitogenesis. ETB receptors are primarily located on endothelial cells, where they stimulate vasodilation via activation of endothelial cell nitric oxide synthesis and ET-1 clearance via receptor-mediated endocytosis. However, some ETB receptors are also located on smooth muscle cells where they mediate vasoconstriction and cellular proliferation. ETA receptor activation is also a powerful stimulus for cardiac myocyte hypertrophy and fibroblast proliferation in the kidneys.
In human blood vessels, 85% of the ET receptor population is made up of ETA receptors, suggesting that antagonism of this receptor alone might be of primary therapeutic benefit. Furthermore, selective antagonism of ETA is thought to be advantageous by preserving the natural vasodilator and clearance responses induced by ET-1 through ETB receptors on endothelial cells.
Based on the results from these animal models, there are several potential clinical indications for ERAs, including pulmonary hypertension, systemic hypertension, chronic kidney disease, and restenosis following angioplasty.
Ambrisentan is (S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid. It is an orally active, non-sulfonamide, propanoic acid-class endothelin receptor antagonist (ERA) that is selective for the endothelin type A (ETA) receptor. The S/R racemic mixture is described for example in Riechers et al., U.S. Pat. No. 7,109,205, the disclosure of which is incorporated by reference. Studies performed in human ventricular tissue with ambrisentan have demonstrated a high affinity (low Ki) for the ETA receptor and a >1000-fold ETA selectivity compared to the ETB receptor. Selective inhibition of the ETA receptor inhibits phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation, while preserving nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance that is associated with the endothelin type B (ETB) receptor.
Ambrisentan has been the subject of clinical testing in humans.
Myogen, Inc. News Release, Dec. 4, 2003 (http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/12-04-2003/0002069898&EDATE=) announced completion of a Phase II trial of ambrisentan in PAH and initiation of Phase III trials. The release stated that the Phase III trials would evaluate 2.5 mg, 5.0 mg and 10.0 mg oral dosages of ambrisentan administered once a day.
Myogen, Inc. News Release, Jan. 8, 2004 (http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=759080&highlight=) announced patient enrollment in phase III clinical trials of ambrisentan for treatment of PAH. According to the news release, phase II trials had demonstrated a statistically significant and clinically meaningful increase in the primary efficacy endpoint (exercise capacity measured by 6MWD) in all four ambrisentan dose groups tested.
Myogen, Inc. News Release, Feb. 16, 2004 (http://investor.myogen.com/phoenix.zhtml ?c=135160&p=irol-newsArticle&ID=759478&highlight=) announced upcoming presentation of detailed results of the phase II study of ambrisentan in PAH, at the American Thoracic Society (ATS) 2004 International Conference. (Rubin (2004) “Ambrisentan Improves Exercise Capacity and Clinical Measures in Pulmonary Arterial Hypertension”, ATS May 21-26, 2004.)
Myogen, Inc. News Release, May 24, 2004 (http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=759469&highlight=) reported improvements in 6MWD, BDI and WHO functional classification seen in the Phase II study. Additionally, the news release mentioned suitability of ambrisentan for once-a-day dosing.
Myogen, Inc. News Release, Feb. 10, 2005 (http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=759971&highlight=) announced that two abstracts describing effects of ambrisentan in patients with PAH were selected for presentation at ATS 2005 in San Diego. (Galié (2005) “Ambrisentan Long-Term Safety and Efficacy in Pulmonary Arterial Hypertension 1-Year Follow-Up”, ATS May 23, 2005; Frost (2005) “Ambrisentan Improves 6MWD Comparably for WHO Class II and III PAH Patients,” ATS May 22, 2005.)
Myogen, Inc. News Release, May 19, 2005 (http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&M=759658&highlight=) reported initiation of a clinical trial to evaluate ambrisentan in patients with PAH who have previously discontinued bosentan or sitaxsentan therapy due to liver function test (LFT) abnormalities, specifically elevated serum aminotransferase concentrations.
Rubin et al. (2005) Future Cardiol. 1(4):1-8 reported improvement of the mean 6MWD for all patients after 12 weeks of ambrisentan treatment, with a mean increase from baseline of 36 meters.
Galié et al. (2005) J. Am. Coll. Cardiol. 46(3):529-535 reported results of a randomized dose-ranging study examining efficacy and safety of ambrisentan in patients with PAH.